Istamycin B.sub.o is an aminoglycosidic antibiotic which was discovered by the present inventors and is produced in the culture broth of Streptomyces tenjimariensis (see Japanse patent application prepublication "Kokai" No. 43295/81; U.K. Pat. No. 2048855; and U.S. Pat. No. 4296106). 3-Demethoxyistamycin B is a new semi-synthetic aminoglycosidic antibiotic which was synthesized by us from istamycin B.sub.o and exhibits a high antibacterial activity against a wide range of gram-negative and gram-positive bacteria, including Pseudomonas aeruginosa (see Japanse Patent application No. 193436/82; EPC patent application No. 83306537.8; and U.S. patent application Ser. No. 545,686). 3-Demethoxyistamycin B is represented by the formula ##STR1##
It is known that a few of aminoglycosidic antibiotic substances are converted into an N-methanesulfonic acid derivative thereof by N-sulfomethylation of some or all of the amino group(s) present in the antibiotic molecule, and that the N-methanesulfonic acid derivative so produced exhibits a lower toxicity than the parent antibiotic. An example is N-methanesulfonic acid derivatives of kanamycin A (Journal of Antibiotics, A 14, page 170 (1961)). Besides, it has been found by the present invention that an N-methanesulfonic acid derivative of 3',4'-dideoxykanamycin B can be synthesized by reaction of 3',4'-dideoxykanamycin B, an aldehyde and sulfurous acid or an alkali metal hydrogen sulfite with each other, and that this N-methanesulfonic acid derivative is of lower toxicity than the parent 3',4'-dideoxykanamycin B and hence is valuable for therapeutic treatment of bacterial infections (see Japanese patent application prepublication "Kokai" No. 39653/77; U.K. Pat. No. 1507118; U.S. Pat. No. 4,091,202). It has also been found by us that an N-methanesulfonic acid derivative of istamycin A or B and that of 3-0-demethylistamycin B may be obtained as new less toxic substances having useful antibacterial activity (see Japanese patent application prepublication "Kokai" No. 40496/82; published U.K. patent application GB 2083464A; U.S. patent application Ser. No. 289,963 for the former and Japanese patent application prepublication "Kokai" No. 128395/83; U.S. patent application Ser. No. 458,824 for the latter).
The discoveries mentioned above are solely related to N-methanesulfonic acid derivatives of kanamycin, istamycins A and B and 3-0-demethylistamycin B and are not extensively applicable to those of all the aminoglycosidic antibiotics.
An object of this invention is to provide a new antibiotic derivative of 3-demethoxyistamycin B which, we have found, retains useful antibacterial activity of 3-demethoxyistamycin B but exhibits a lower toxicity than that of 3-demethoxyistamycin B itself. The other object is to provide a process for the preparation of such new antibiotic derivative of 3-demethoxyistamycin B. Another objects of this invention will be clear from the following descriptions.
As a result of our research, we have now found that as new compounds or substances, N-methanesulfonic acid derivatives of 3-demethoxyistamycin B can be synthesized by reaction of 3-demethoxyistamycin B of the above formula (I) or a partial acid addition salt thereof with an aldehyde of the formula: EQU RCHO (IV)
wherein R is as defined later and also with sulfurous acid or an alkali or alkaline earth metal hydrogen sulfite or ammonium hydrogen sulfite of the formula: EQU MHSO.sub.3 (V)
wherein M is a hydrogen atom, an alkali metal, alkaline earth metal atom or ammonium cation. We have confirmed that these N-methanesulfonic acid derivatives of 3-demethoxyistamycin B are of remarkedly lower toxicity than 3-demethoxyistamycin B itself. 3-Demethoxyistamycin B contains three amino groups and one methylamino group per molecule as will be clear from the above formula (I), and it has been found that the new N-methanesulfonic acid derivative of 3-demethoxyistamycin B so prepared is such one in which one, two, three or four groups of the aforesaid three amino groups and one methylamino group present in the molecule has or have been N-sulfomethylated, that is to say, substituted with a methanesulfonate group of the formula: EQU --CHRSO.sub.3 M (II)
wherein R is a hydrogen atom, an alkyl group, preferably an alkyl group of 1-4 carbon atoms, a substituted alkyl group, a phenyl group or a substituted phenyl group, and M represents a hydrogen atom, an ammonium cation, an alkali metal or an alkaline earth metal atom. The total number of the N-sulfomethylated amino and methylamino groups present in the resulting N-methanesulfonic acid derivative of 3-demethoxyistamycin B amounts to 1, 2, 3 or 4, depending upon the molar proportions of the aldehyde and the sulfurous acid or sulfite compound employed for 1 molar proportion of 3-demethoxyistamycin B.